HIV is transmitted primarily across surfaces of the genital and anorectal mucosa, however, epidemiologic evidence suggests that transmission across the oropharyngeal or gastrointestinal mucosa occurs in adults through oral-genital contact, and in neonates through ingestion of maternal blood or cervicovaginal secretions during birth, or through ingestion of colostrurn Or milk from infected mothers. Because neonatal infection following oral exposure to HP/ is likely to play a significant role in the HIV epidemic, it is important to understand the mechanism of oral transmission in neonates. Infection of macaques with simian immunodeficiency virus (SW) provides a useful model for investigating important issues associated with HIV pathogenesis. We have isolated a pathogenic, macrophage-tropic SW (SIVsmmFGb) from a sooty mangabey monkey that is readily transmitted by oral inoculation. The long-term objective of this proposal is to elucidate the mechanism of HIV transmission across the mucosa of the oral cavity and gastrointestinal tract (Off), using the SIVsmmFGb model. Initial experiments are designed to identify the anatomic sites of viral transmission following oral inoculation of both adult and neonatal pigtailed macaques. We hypothesize that transmission will occur at multiple sites within the alimentary tract, including the lymphoepithelium of the tonsil, the respiratory mucosa of the nasopharynx, and the columnar epithelium of the gastrointestinal tract. In our second specific aim, we will identify the initial target cells of infection following oral inoculation. We hypothesize that CD4+ T cells are the primary targets of productive infection at all portals of viral entry, although macrophages are also infected. In addition, we hypothesize that Langerhans dendritic cells are permissive for infection, and conduct virus from the oropharynx to activated CD4+ T cells in the tonsil and retropharyngeal lymph node. HIV is found in both cell-free and cell- associated fractions of human breast milk from HIV positive women, however, the relative contributions of cell-free versus cell-associated virus to the infection of nursing neonates is unknown. In our third specific aim, we will investigate whether cell-associated SIV is capable of initiating infection across the alimentary mucosa of neonatal macaques following oral inoculation. We hypothesize that infected macrophages and/or dendritic cells must be present in cell-associated inocula in order to initiate mucosal infection.